Skip to main content
NCBI home page
Journal of Medical Genetics logoLink to Journal of Medical Genetics
. 2001 Jan;38(1):26–34. doi: 10.1136/jmg.38.1.26

Molecular characterisation of four cases of intrachromosomal triplication of chromosome 15q11-q14

P Ungaro 1, S Christian 1, J Fantes 1, A Mutirangura 1, S Black 1, J Reynolds 1, S Malcolm 1, W Dobyns 1, D Ledbetter 1
PMCID: PMC1734721  PMID: 11134237

Abstract

CONTEXT—Chromosomal abnormalities that involve the proximal region of chromosome 15q occur relatively frequently in the human population. However, interstitial triplications involving one 15 homologue are very rare with three cases reported to date.
OBJECTIVE—To provide a detailed molecular characterisation of four additional patients with interstitial triplications of chromosome 15q11-q14.
DESIGN—Molecular analyses were performed using DNA markers and probes specific for the 15q11-q14 region.
SETTING—Molecular cytogenetics laboratory at the University of Chicago.
SUBJECTS—Four patients with mild to severe mental retardation and features of Prader-Willi syndrome (PWS) or Angelman syndrome (AS) were referred for molecular cytogenetic analysis following identification of a suspected duplication/triplication of chromosome 15q11-q14 by routine cytogenetic analysis.
MAIN OUTCOME MEASURES—Fluorescence in situ hybridisation (FISH) was performed to determine the type of chromosomal abnormality present, the extent of the abnormal region, and the orientation of the extra chromosomal segments. Molecular polymorphism analysis was performed to determine the parental origin of the abnormality. Methylation and northern blot analyses of the SNRPN gene were performed to determine the effect of extra copies of the SNRPN gene on its methylation pattern and expression.
RESULTS—Fluorescence in situ hybridisation (FISH) using probes within and flanking the Prader-Willi/Angelman syndrome critical region indicated that all patients carried an intrachromosomal triplication of proximal 15q11-q14 in one of the two chromosome 15 homologues (trip(15)). In all patients the orientation of the triplicated segments was normal-inverted-normal, suggesting that a common mechanism of rearrangement may have been involved. Microsatellite analysis showed the parental origin of the trip(15) to be maternal in three cases and paternal in one case. The paternal triplication patient had features similar to PWS, one maternal triplication patient had features similar to AS, and the other two maternal triplication patients had non-specific findings including hypotonia and mental retardation. Methylation analysis at exon 1 of the SNRPN locus showed increased dosage of either the paternal or maternal bands in the paternal or maternal triplication patients, respectively, suggesting that the methylation pattern shows a dose dependent increase that correlates with the parental origin of the triplication. In addition, the expression of SNRPN was analysed by northern blotting and expression levels were consistent with dosage and parental origin of the triplication.
CONCLUSIONS—These four additional cases of trip(15) will provide additional information towards understanding the phenotypic effects of this abnormality and aid in understanding the mechanism of formation of other chromosome 15 rearrangements.


Keywords: chromosome 15 triplication; Prader-Willi syndrome; Angelman syndrome; autism

Full Text

The Full Text of this article is available as a PDF (271.5 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Barbu V., Dautry F. Northern blot normalization with a 28S rRNA oligonucleotide probe. Nucleic Acids Res. 1989 Sep 12;17(17):7115–7115. doi: 10.1093/nar/17.17.7115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Boccaccio I., Glatt-Deeley H., Watrin F., Roëckel N., Lalande M., Muscatelli F. The human MAGEL2 gene and its mouse homologue are paternally expressed and mapped to the Prader-Willi region. Hum Mol Genet. 1999 Dec;8(13):2497–2505. doi: 10.1093/hmg/8.13.2497. [DOI] [PubMed] [Google Scholar]
  3. Browne C. E., Dennis N. R., Maher E., Long F. L., Nicholson J. C., Sillibourne J., Barber J. C. Inherited interstitial duplications of proximal 15q: genotype-phenotype correlations. Am J Hum Genet. 1997 Dec;61(6):1342–1352. doi: 10.1086/301624. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bundey S., Hardy C., Vickers S., Kilpatrick M. W., Corbett J. A. Duplication of the 15q11-13 region in a patient with autism, epilepsy and ataxia. Dev Med Child Neurol. 1994 Aug;36(8):736–742. doi: 10.1111/j.1469-8749.1994.tb11916.x. [DOI] [PubMed] [Google Scholar]
  5. Chong S. S., Pack S. D., Roschke A. V., Tanigami A., Carrozzo R., Smith A. C., Dobyns W. B., Ledbetter D. H. A revision of the lissencephaly and Miller-Dieker syndrome critical regions in chromosome 17p13.3. Hum Mol Genet. 1997 Feb;6(2):147–155. doi: 10.1093/hmg/6.2.147. [DOI] [PubMed] [Google Scholar]
  6. Christian S. L., Bhatt N. K., Martin S. A., Sutcliffe J. S., Kubota T., Huang B., Mutirangura A., Chinault A. C., Beaudet A. L., Ledbetter D. H. Integrated YAC contig map of the Prader-Willi/Angelman region on chromosome 15q11-q13 with average STS spacing of 35 kb. Genome Res. 1998 Feb;8(2):146–157. doi: 10.1101/gr.8.2.146. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Christian S. L., Fantes J. A., Mewborn S. K., Huang B., Ledbetter D. H. Large genomic duplicons map to sites of instability in the Prader-Willi/Angelman syndrome chromosome region (15q11-q13). Hum Mol Genet. 1999 Jun;8(6):1025–1037. doi: 10.1093/hmg/8.6.1025. [DOI] [PubMed] [Google Scholar]
  8. Christian S. L., Robinson W. P., Huang B., Mutirangura A., Line M. R., Nakao M., Surti U., Chakravarti A., Ledbetter D. H. Molecular characterization of two proximal deletion breakpoint regions in both Prader-Willi and Angelman syndrome patients. Am J Hum Genet. 1995 Jul;57(1):40–48. [PMC free article] [PubMed] [Google Scholar]
  9. Clayton-Smith J., Webb T., Cheng X. J., Pembrey M. E., Malcolm S. Duplication of chromosome 15 in the region 15q11-13 in a patient with developmental delay and ataxia with similarities to Angelman syndrome. J Med Genet. 1993 Jun;30(6):529–531. doi: 10.1136/jmg.30.6.529. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Cook E. H., Jr, Lindgren V., Leventhal B. L., Courchesne R., Lincoln A., Shulman C., Lord C., Courchesne E. Autism or atypical autism in maternally but not paternally derived proximal 15q duplication. Am J Hum Genet. 1997 Apr;60(4):928–934. [PMC free article] [PubMed] [Google Scholar]
  11. Crolla J. A., Harvey J. F., Sitch F. L., Dennis N. R. Supernumerary marker 15 chromosomes: a clinical, molecular and FISH approach to diagnosis and prognosis. Hum Genet. 1995 Feb;95(2):161–170. doi: 10.1007/BF00209395. [DOI] [PubMed] [Google Scholar]
  12. Feinberg A. P., Vogelstein B. "A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity". Addendum. Anal Biochem. 1984 Feb;137(1):266–267. doi: 10.1016/0003-2697(84)90381-6. [DOI] [PubMed] [Google Scholar]
  13. Gabriel J. M., Higgins M. J., Gebuhr T. C., Shows T. B., Saitoh S., Nicholls R. D. A model system to study genomic imprinting of human genes. Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14857–14862. doi: 10.1073/pnas.95.25.14857. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Glenn C. C., Saitoh S., Jong M. T., Filbrandt M. M., Surti U., Driscoll D. J., Nicholls R. D. Gene structure, DNA methylation, and imprinted expression of the human SNRPN gene. Am J Hum Genet. 1996 Feb;58(2):335–346. [PMC free article] [PubMed] [Google Scholar]
  15. Gray T. A., Saitoh S., Nicholls R. D. An imprinted, mammalian bicistronic transcript encodes two independent proteins. Proc Natl Acad Sci U S A. 1999 May 11;96(10):5616–5621. doi: 10.1073/pnas.96.10.5616. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Greger V., Knoll J. H., Wagstaff J., Woolf E., Lieske P., Glatt H., Benn P. A., Rosengren S. S., Lalande M. Angelman syndrome associated with an inversion of chromosome 15q11.2q24.3. Am J Hum Genet. 1997 Mar;60(3):574–580. [PMC free article] [PubMed] [Google Scholar]
  17. Horsthemke B., Maat-Kievit A., Sleegers E., van den Ouweland A., Buiting K., Lich C., Mollevanger P., Beverstock G., Gillessen-Kaesbach G., Schwanitz G. Familial translocations involving 15q11-q13 can give rise to interstitial deletions causing Prader-Willi or Angelman syndrome. J Med Genet. 1996 Oct;33(10):848–851. doi: 10.1136/jmg.33.10.848. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Huang B., Crolla J. A., Christian S. L., Wolf-Ledbetter M. E., Macha M. E., Papenhausen P. N., Ledbetter D. H. Refined molecular characterization of the breakpoints in small inv dup(15) chromosomes. Hum Genet. 1997 Jan;99(1):11–17. doi: 10.1007/s004390050301. [DOI] [PubMed] [Google Scholar]
  19. Jay P., Rougeulle C., Massacrier A., Moncla A., Mattei M. G., Malzac P., Roëckel N., Taviaux S., Lefranc J. L., Cau P. The human necdin gene, NDN, is maternally imprinted and located in the Prader-Willi syndrome chromosomal region. Nat Genet. 1997 Nov;17(3):357–361. doi: 10.1038/ng1197-357. [DOI] [PubMed] [Google Scholar]
  20. Jong M. T., Gray T. A., Ji Y., Glenn C. C., Saitoh S., Driscoll D. J., Nicholls R. D. A novel imprinted gene, encoding a RING zinc-finger protein, and overlapping antisense transcript in the Prader-Willi syndrome critical region. Hum Mol Genet. 1999 May;8(5):783–793. doi: 10.1093/hmg/8.5.783. [DOI] [PubMed] [Google Scholar]
  21. Knoll J. H., Nicholls R. D., Magenis R. E., Glatt K., Graham J. M., Jr, Kaplan L., Lalande M. Angelman syndrome: three molecular classes identified with chromosome 15q11q13-specific DNA markers. Am J Hum Genet. 1990 Jul;47(1):149–154. [PMC free article] [PubMed] [Google Scholar]
  22. Kubota T., Das S., Christian S. L., Baylin S. B., Herman J. G., Ledbetter D. H. Methylation-specific PCR simplifies imprinting analysis. Nat Genet. 1997 May;16(1):16–17. doi: 10.1038/ng0597-15. [DOI] [PubMed] [Google Scholar]
  23. Kuwano A., Mutirangura A., Dittrich B., Buiting K., Horsthemke B., Saitoh S., Niikawa N., Ledbetter S. A., Greenberg F., Chinault A. C. Molecular dissection of the Prader-Willi/Angelman syndrome region (15q11-13) by YAC cloning and FISH analysis. Hum Mol Genet. 1992 Sep;1(6):417–425. doi: 10.1093/hmg/1.6.417. [DOI] [PubMed] [Google Scholar]
  24. Leana-Cox J., Jenkins L., Palmer C. G., Plattner R., Sheppard L., Flejter W. L., Zackowski J., Tsien F., Schwartz S. Molecular cytogenetic analysis of inv dup(15) chromosomes, using probes specific for the Prader-Willi/Angelman syndrome region: clinical implications. Am J Hum Genet. 1994 May;54(5):748–756. [PMC free article] [PubMed] [Google Scholar]
  25. Long F. L., Duckett D. P., Billam L. J., Williams D. K., Crolla J. A. Triplication of 15q11-q13 with inv dup(15) in a female with developmental delay. J Med Genet. 1998 May;35(5):425–428. doi: 10.1136/jmg.35.5.425. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Maraschio P., Zuffardi O., Bernardi F., Bozzola M., De Paoli C., Fonatsch C., Flatz S. D., Ghersini L., Gimelli G., Loi M. Preferential maternal derivation in inv dup(15): analysis of eight new cases. Hum Genet. 1981;57(4):345–350. doi: 10.1007/BF00281681. [DOI] [PubMed] [Google Scholar]
  27. Meguro M., Mitsuya K., Sui H., Shigenami K., Kugoh H., Nakao M., Oshimura M. Evidence for uniparental, paternal expression of the human GABAA receptor subunit genes, using microcell-mediated chromosome transfer. Hum Mol Genet. 1997 Nov;6(12):2127–2133. doi: 10.1093/hmg/6.12.2127. [DOI] [PubMed] [Google Scholar]
  28. Mutirangura A., Greenberg F., Butler M. G., Malcolm S., Nicholls R. D., Chakravarti A., Ledbetter D. H. Multiplex PCR of three dinucleotide repeats in the Prader-Willi/Angelman critical region (15q11-q13): molecular diagnosis and mechanism of uniparental disomy. Hum Mol Genet. 1993 Feb;2(2):143–151. doi: 10.1093/hmg/2.2.143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Nicholls R. D., Saitoh S., Horsthemke B. Imprinting in Prader-Willi and Angelman syndromes. Trends Genet. 1998 May;14(5):194–200. doi: 10.1016/s0168-9525(98)01432-2. [DOI] [PubMed] [Google Scholar]
  30. Ozçelik T., Leff S., Robinson W., Donlon T., Lalande M., Sanjines E., Schinzel A., Francke U. Small nuclear ribonucleoprotein polypeptide N (SNRPN), an expressed gene in the Prader-Willi syndrome critical region. Nat Genet. 1992 Dec;2(4):265–269. doi: 10.1038/ng1292-265. [DOI] [PubMed] [Google Scholar]
  31. Pettigrew A. L., Gollin S. M., Greenberg F., Riccardi V. M., Ledbetter D. H. Duplication of proximal 15q as a cause of Prader-Willi syndrome. Am J Med Genet. 1987 Dec;28(4):791–802. doi: 10.1002/ajmg.1320280403. [DOI] [PubMed] [Google Scholar]
  32. Repetto G. M., White L. M., Bader P. J., Johnson D., Knoll J. H. Interstitial duplications of chromosome region 15q11q13: clinical and molecular characterization. Am J Med Genet. 1998 Sep 1;79(2):82–89. doi: 10.1002/(sici)1096-8628(19980901)79:2<82::aid-ajmg2>3.0.co;2-p. [DOI] [PubMed] [Google Scholar]
  33. Robinson W. P., Binkert F., Giné R., Vazquez C., Müller W., Rosenkranz W., Schinzel A. Clinical and molecular analysis of five inv dup(15) patients. Eur J Hum Genet. 1993;1(1):37–50. doi: 10.1159/000472386. [DOI] [PubMed] [Google Scholar]
  34. Robinson W. P., Dutly F., Nicholls R. D., Bernasconi F., Peñaherrera M., Michaelis R. C., Abeliovich D., Schinzel A. A. The mechanisms involved in formation of deletions and duplications of 15q11-q13. J Med Genet. 1998 Feb;35(2):130–136. doi: 10.1136/jmg.35.2.130. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Rougeulle C., Glatt H., Lalande M. The Angelman syndrome candidate gene, UBE3A/E6-AP, is imprinted in brain. Nat Genet. 1997 Sep;17(1):14–15. doi: 10.1038/ng0997-14. [DOI] [PubMed] [Google Scholar]
  36. Schinzel A. A., Brecevic L., Bernasconi F., Binkert F., Berthet F., Wuilloud A., Robinson W. P. Intrachromosomal triplication of 15q11-q13. J Med Genet. 1994 Oct;31(10):798–803. doi: 10.1136/jmg.31.10.798. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Schroer R. J., Phelan M. C., Michaelis R. C., Crawford E. C., Skinner S. A., Cuccaro M., Simensen R. J., Bishop J., Skinner C., Fender D. Autism and maternally derived aberrations of chromosome 15q. Am J Med Genet. 1998 Apr 1;76(4):327–336. doi: 10.1002/(sici)1096-8628(19980401)76:4<327::aid-ajmg8>3.0.co;2-m. [DOI] [PubMed] [Google Scholar]
  38. Slizynska H. Triplications and the problem of non-homologous crossing-over. Genet Res. 1968 Apr;11(2):201–208. doi: 10.1017/s001667230001137x. [DOI] [PubMed] [Google Scholar]
  39. Sutcliffe J. S., Jiang Y. H., Galijaard R. J., Matsuura T., Fang P., Kubota T., Christian S. L., Bressler J., Cattanach B., Ledbetter D. H. The E6-Ap ubiquitin-protein ligase (UBE3A) gene is localized within a narrowed Angelman syndrome critical region. Genome Res. 1997 Apr;7(4):368–377. doi: 10.1101/gr.7.4.368. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Sutcliffe J. S., Nakao M., Christian S., Orstavik K. H., Tommerup N., Ledbetter D. H., Beaudet A. L. Deletions of a differentially methylated CpG island at the SNRPN gene define a putative imprinting control region. Nat Genet. 1994 Sep;8(1):52–58. doi: 10.1038/ng0994-52. [DOI] [PubMed] [Google Scholar]
  41. Wandstrat A. E., Leana-Cox J., Jenkins L., Schwartz S. Molecular cytogenetic evidence for a common breakpoint in the largest inverted duplications of chromosome 15. Am J Hum Genet. 1998 Apr;62(4):925–936. doi: 10.1086/301777. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Wang J., Reddy K. S., Wang E., Halderman L., Morgan B. L., Lachman R. S., Lin H. J., Cornford M. E. Intrachromosomal triplication of 2q11.2-q21 in a severely malformed infant: case report and review of triplications and their possible mechanism. Am J Med Genet. 1999 Feb 12;82(4):312–317. doi: 10.1002/(sici)1096-8628(19990212)82:4<312::aid-ajmg7>3.0.co;2-9. [DOI] [PubMed] [Google Scholar]
  43. Webb T. Inv dup(15) supernumerary marker chromosomes. J Med Genet. 1994 Aug;31(8):585–594. doi: 10.1136/jmg.31.8.585. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Wevrick R., Kerns J. A., Francke U. Identification of a novel paternally expressed gene in the Prader-Willi syndrome region. Hum Mol Genet. 1994 Oct;3(10):1877–1882. doi: 10.1093/hmg/3.10.1877. [DOI] [PubMed] [Google Scholar]
  45. Wisniewski L., Hassold T., Heffelfinger J., Higgins J. V. Cytogenetic and clinical studies in five cases of inv dup(15). Hum Genet. 1979 Sep;50(3):259–270. doi: 10.1007/BF00399391. [DOI] [PubMed] [Google Scholar]
  46. Zeschnigk M., Schmitz B., Dittrich B., Buiting K., Horsthemke B., Doerfler W. Imprinted segments in the human genome: different DNA methylation patterns in the Prader-Willi/Angelman syndrome region as determined by the genomic sequencing method. Hum Mol Genet. 1997 Mar;6(3):387–395. doi: 10.1093/hmg/6.3.387. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Medical Genetics are provided here courtesy of BMJ Publishing Group

RESOURCES